review of the fact: analytic strategies to improve sensitivity

Review of the FACT: Analytic Strategies to Improve Sensitivity

David Cella, Ph.D.Evanston Northwestern Healthcare

and Northwestern University

www.facit.org

Buchanan et al, JCO, 2005

• QOL assessment in Sx trials is rising without good justification

• Single symptom improvement often fails to improve overall QOL

• Acceptable rationales– Gauge importance patients assign to symptom relief– Gain dx information about offsetting tx effects– Advance a compelling conceptual model of the

relationship between symptoms and QOL

04/22/23

Conceptual Framework: Relationship Conceptual Framework: Relationship Among Patient Outcome MeasuresAmong Patient Outcome Measures

Biological and PhysiologicalVariables

Symptoms Functional Status

GeneralHealth Perceptions

Overall QOL

Characteristics of the Individual

Characteristics of the Environment

Values / Preferences

From: Wilson & Cleary (1995)

Symptom-targeted interventions can have overall QOL benefits

FACT-G changes overtime

-4-202468

10

Baseline 1-3 months 4-5 months after 6 monthsFAC

T-G

diff

eren

ce (s

core

ove

r tim

e -

scor

e at

bas

elin

e)

Intervention Attention-control Control

Velikova et al., JCO, 2004.

Some, not all, benefit in emotional well-being

Changes in FACT-EWB over time

-0.50

0.51

1.52

2.5

Baseline 1-3 months 4-5 months After 6months

FA

CT

-EW

B d

iffe

ren

ce

(s

co

re o

ve

r ti

me

- s

co

re a

t b

as

elin

e)

Intervention Attention-control Control

Velikova et al., JCO, 2004.

Some studies actually suggest overall QOL benefit without target

symptom benefit

• Osterborg, JCO, 2002– Placebo vs epo beta for CIA– No difference in FACIT-Fatigue– Significant difference in overall QOL

QOL Model

HRQoLHRQoL

PWBPWB MWBMWB SWBSWB

Total/OverallTotal/Overall(aggregated)(aggregated)

GlobalGlobal(synthesized)(synthesized)

Adapted from WHO

Symptoms Function Symptoms Function Concerns Function

Overall versus Global HRQLBoth have problems in symptom trials

• Overall (Total score)– Tension between content validity and focused

relevance– Unresponsiveness caused by mistargeted questions

• Global rating– Intuitively appealing but coarse– Vulnerable to several cognitive biases that affect

reporting of general well-being and satisfaction

Are we doomed to be happy?• Life satisfaction research consistently places people near

the 75% of satisfaction/happiness scales• Short term improvements in environmental conditions,

wealth, etc, have a modest effect• Most human happiness is independent of life’s ups and

downs• Implications for measuring GLOBAL QOL in cancer

trials– May see small short term benefits, unlikely to see lasting effect

– Background noise caused by positive cognitive bias

– Background noise caused by “doing something”

Thoughts drawn from Cummins & Nistico, 2002

General Population NormsMales and Females Combined

(N=1075)

T-S

core

0

10

20

30

40

50

60

70

0 1 2 3 4 5 6Well Being

Physical

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

Social / FamilyWell Being

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Mean for Cancer Patients

Well BeingEmotional

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

Well BeingFunctional

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

0

10

20

30

40

46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98100102104106108

FACT-GTotal

5

15

25

35

45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97 99101103105107

FACT Profile of Cancer Patients (n=2,236) Referenced to General Population (n=1,075)

Symptom Prevalence Among Patients with Cancer or HIV

0 20 40 60 80 100

Fatigue

Pain

Anxiety

Depression

Nausea

HIV (n=433) Cancer (n=2791)

Cella D, 1998Percentage Reporting Symptom, any severity

FACT/NCCN Survey ResultsNumber of times symptom is in “top 5”

lack of energy (fatigue) 9/9

pain 8/9

nausea 7/9

losing weight 5/9

worry condition worse 5/9

content w/ QOL 4/9

certain areas experience pain 3/9

swelling/cramps in stomach 3/9

able to enjoy life 2/9

short of breath 2/9

trouble meeting needs of family 2/9

Clinically Significant Symptoms in NSCLC Patients With Provider-Rated PS0-1 at Baseline (E5592)

0

5

10

15

20

25

30

35

40

45

Baseline 6 weeks 12 weeks 6 months

Fatigue Pain Weight loss Appetite loss

Clin

ically S

ign

ifican

t S

ym

pto

ms (

%)

Clinically Significant Symptoms in NSCLC Patients With Provider-Rated PS0-1 at Baseline (E5592)

0

5

10

15

20

25

30

35

40

45

Baseline 6 weeks 12 weeks 6 months

Depression Hopelessness Anhedonia Bothered by treatment side effects

Clin

ically

Sig

nifi

cant

Sym

pto

ms

(%)

Symptoms and QOL (N=1,163)

50

60

70

80

90

100

Very much Quite a bit A little Not at all

FA

CT

-G T

otal

pain

insomnia

weakness

nausea

Diarrhea

Side Effect Bother and QOL

50

60

70

80

90

100

Very much Quite a bit Somewhat A little Not at all

FAC

T-G

(2

6-i

tem

s)

Breast (n=529)

Colon (n=254)

Head/Neck (n=233)

FACIT measurement systemFACIT measurement system

Functional Assessment of Chronic

Illness TherapyAn array of multidimensional self-report

quality-of-life questionnaires

Over 400 itemsOver 400 items

Over 50 languages (selected scales)Over 50 languages (selected scales)

Over 30 targeted subscalesOver 30 targeted subscales

www.facit.org

Disease Symptoms

Emotional

Physical

Social

Functional

Framework for FACT

Trial Outcome Index = Physical + Functional + Symptoms

(e.g., 36-item FACT-L includes 17 symptoms)

FACT-G (Version 4)FACT-G (Version 4)Below is a list of statements that other people with your illness have said Below is a list of statements that other people with your illness have said

are important. By circling one (1) number per line, please indicate how true are important. By circling one (1) number per line, please indicate how true each statement has been for you each statement has been for you during the past 7 daysduring the past 7 days

Physical wellbeingPhysical wellbeing

GP1GP1 I have a lack of energyI have a lack of energyGP2GP2 I have nauseaI have nausea

GP3GP3 Because of my physical Because of my physical condition, I have troublecondition, I have troublemeeting the needs of mymeeting the needs of myfamilyfamily

GP4GP4 I have painI have pain

GP5GP5 I am bothered by side I am bothered by side effects of treatmenteffects of treatment

GP6GP6 I feel illI feel ill

GP7GP7 I am forced to spend I am forced to spend time in bedtime in bed

Not at allNot at all

0000

00

00

00

00

00

A little bitA little bit

1111

11

11

11

11

11

SomewhatSomewhat

2222

22

22

22

22

22

Quite a bitQuite a bit

3333

33

33

33

33

33

Very muchVery much

4444

44

44

44

44

44

FACT Cancer-Specific Scales

• Breast cancer• Bladder cancer• Brain tumor• Colorectal cancer• CNS cancer• Cervical cancer• Esophageal cancer• Endometrial cancer

• Head and neck cancer• Hepatobiliary cancer• Lung cancer• Leukemia• Lymphoma• Ovarian cancer• Prostate cancer• Vulvar cancer

www.facit.orgwww.facit.org

FACT-Lung SubscaleFACT-Lung Subscale

• I have been short of breath

• I am losing weight

• My thinking is clear

• I have been coughing

• I have a good appetite

• I feel tightness in my chest

• Breathing is easy for me

Short of breathShort of breath Self-conscious about dressSelf-conscious about dress One or both arms swollen or tenderOne or both arms swollen or tender Sexually attractiveSexually attractive Bothered by hair lossBothered by hair loss Other family members might get same illnessOther family members might get same illness Effect of stress on illnessEffect of stress on illness Bothered by change in weightBothered by change in weight Feel like a womanFeel like a woman

FACT-Breast Subscale

FACIT symptom-specific subscalesFACIT symptom-specific subscales

AnemiaAnemiaAnorexia/cachexiaAnorexia/cachexia

DiarrheaDiarrhea

FatigueFatigue

Endocrine symptomsEndocrine symptoms

Fecal incontinenceFecal incontinence

Urinary incontinenceUrinary incontinence

Fatigue subscaleFatigue subscale Feel fatiguedFeel fatigued Feel weak all over Feel weak all over Feel listless Feel listless Feel tiredFeel tired Have trouble starting things Have trouble starting things Have trouble finishing things Have trouble finishing things Have no energyHave no energy Able to do usual activities Able to do usual activities Require sleep during day Require sleep during day Too tired to eat Too tired to eat Need help doing usual activitiesNeed help doing usual activities Frustrated/too tired for usual activitiesFrustrated/too tired for usual activities Must limit social activity because too tiredMust limit social activity because too tired

04/22/23

Littlewood et al (JCO 2000) Epoetin alfa Trial Treatment Schema

150 IU/kg (if Hb 150 IU/kg (if Hb 1 g/dL or 1 g/dL or reticulocytes reticulocytes 40,000/40,000/L) L) at Week 4at Week 4

300 IU/kg (if Hb 300 IU/kg (if Hb <1 g/dL and <1 g/dL andreticulocytes reticulocytes <40,000/ <40,000/L)L)at Week 4at Week 4

Chemo-Chemo-therapy*therapy*

44 88 1212 1616 2020 2424 282800

PlaceboPlacebo

WeeksWeeks

150 IU/kg 150 IU/kg epoetin alfa epoetin alfa

ororPlacebo (if Hb Placebo (if Hb 1 g/dL or 1 g/dL or reticulocytes reticulocytes 40,000/40,000/L) L) at Week 4at Week 4

Double placebo (if Hb Double placebo (if Hb <1 g/dL and <1 g/dL andreticulocytes reticulocytes <40,000/ <40,000/L) L) at Week 4at Week 4

*Chemotherapy duration 3-6 cycles; includes 3-4 weeks after the last dose of chemotherapy*Chemotherapy duration 3-6 cycles; includes 3-4 weeks after the last dose of chemotherapy

04/22/23

FACT-G, FACT-An: Fatigue, andFACT-An: Anemia Scores

Change From Baseline to Last Assessment

-5

0

5

n=192

n=87

n=200

n=90

n=200

n=90

FACT-G:TotalP<.05

FACT-An:FatigueP<.01

FACT-An:AnemiaP<.01*

Ch

ang

e in

Sco

re

Epoetin alfa Placebo

2.42

-3.31

2.97

-2.18

4.02

-2.64

Decrease in FACT-G Total Vs No History of Specified Illnesses

(-0.34) (0) (0.34) (0.69) (1.03) (1.37) 1.71)

Decrease in FACTG (Effect size)

Baseline

FinalAssessment

FACIT-Fatigue Subscale

26 31 36 41 46

His

tory

of C

ance

r

His

tory

of C

ance

r

No

His

tory

of I

llnes

s

No

Hist

ory i

f Illn

ess

Plac

ebo

His

tory

of A

nem

ia

EPO

EPO His

tory

of A

nem

ia

Plac

ebo

All Res

pond

ents

All Res

pond

ents

EPO = Erythhropoeitin

Baseline

FinalAssessment

FACT-G Total

68 73 78 83 88

His

tory

of C

ance

r

His

tory

of C

ance

r

No

His

tory

of I

llnes

s

No

Hist

ory o

f Illn

ess

Plac

ebo

His

tory

of A

nem

ia

EPO

EPOHis

tory

of A

nem

ia

Plac

ebo

All

Res

pond

ents

All

Res

pond

ents

EPO = Erythhropoeitin

FACT-Endocrine Symptoms Subscale Hot flashes Hot flashes Cold sweatsCold sweats Night sweatsNight sweats Vaginal dischargeVaginal discharge Vaginal itching/irritationVaginal itching/irritation Vaginal bleeding or spottingVaginal bleeding or spotting Vaginal drynessVaginal dryness Pain or discomfort with intercoursePain or discomfort with intercourse Lost interest in sexLost interest in sex Gained weightGained weight Lightheaded/dizzyLightheaded/dizzy VomitingVomiting BloatedBloated Breast sensitivity/tendernessBreast sensitivity/tenderness Mood swingsMood swings IrritableIrritable

3Entry 6 12 18 24

75

74

73

72

71

70

69

68

67

66

Visit (months)

Mea

n TO

I

AnastrozoleTamoxifenCombination

324331319

287304281

288309285

267276264

249252250

239 244242

ATAC Trial: Trial Outcome Index

Fallowfield et al. 2002, 2003Fallowfield et al, JCO, 2004

ATAC Trial: FACT-ES Scores

3Entry 6 12 18 24

64

62

60

59

57

Visit (months)

Mea

n E

S

63

61

58

322

330

323286309286

292306295

271279269

252254257

244249241

AnastrozoleTamoxifenCombination

Fallowfield et al. 2002, 2003Fallowfield et al, JCO, 2004

ATAC Trial: Specific Symptoms

Fallowfield et al. 2002, 2003Fallowfield et al, JCO, 2004

0 5 10 15 20 25 300.0

0.2

0.4

0.6

0.8

1.0Probability

Log rank p=0.034Wilcoxon p=0.012

CP/CP+GCE

Time (months)

E 5592: Overall Survival

Baseline to 12-week change in LCS score by best overall response

-2

-1

0

1

2

3

CR/PR (n=95) SD (n=82) PD (n=102)

Best response to treatment

CR/PR > PD

LCS change

CR/PR, complete response/partial response; SD, stable disease; PD, progressive diseaseTime to completion was 12 weeks Cella et al, JCE, 2002

Baseline to 12-week change in LCS score by time to progression

-2

-1

0

1

2 Late > EarlyLCSchange

Late (>116 days)

(n=196)

Early (<116 days)

(n=69)

Time to progression

Time to completion was 12 weeks Cella et al, JCE, 2002.

E5592 - Lung Cancer SubscaleProgression status

10

12

14

16

18

20

22

24

base. 6 wk 12 wk

Laterprogressors

Earlyprogressors

(Range: 0-28)

FACT Symptom Indexes:Undoing the Original Structure

• Most FACT site-specific scales assess about 50% symptoms and 50% function/perception

• FACT-G includes most common symptoms (e.g., pain; fatigue; nausea)

• FACT disease subscales focus on sympoms unique to that condition

• Common and unique need to be brought together to index the symptom burden of each specific cancer

Colorectal Distribution of Items (n=66)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

losing hope

worry condition worse

able to work

control of bowels

spend time in bed

feel ill

enjoy life

content w/ QOL

good appetite

swelling/cramps in stomach

nausea

diarrhea

pain

losing weight

lack of energy (fatigue)

Ite

ms

% Endorsed (top 5)

(chance probability=21%)

Head and NeckDistribution of Items (n=65)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

trouble meeting needs of family

worry about dying

eat foods I like

losing hope

unhappy w/ appearance of face/neck

worry condition worse

content w/ QOL

eat solid foods

nausea

communicate w/ others

trouble breathing

pain in face/neck

lack of energy (fatigue)

swallow naturally/easily

pain

Item

s

% Endorsed (top 5)

(chance probability=19%)

Ovarian Distribution of Items (n=60)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

losing hope

good appetite

spend time in bed

able to enjoy life

control of bow els

trouble meeting needs of family

w orry about dying

feel ill

losing w eight

cramps in stomach

content w / QOL

w orry condition w orse

sw elling in stomach

nausea

pain

vomiting

lack of energy (fatigue)

Ite

ms

% Endorsed (top 5)

(Chance probability=19%)

Lung Distribution of Items (n=66)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

worry about dying

good appetite

tightness in my chest

nausea

able to enjoy life

spend time in bed

content w/ QOL

breathing easy for me

bone pain

coughing

losing weight

pain

lack of energy (fatigue)

short of breath

Item

s

% Endorsed (top 5)

(chance probability=20%)

Why is more precision needed?• Cancer is many diseases and has many effects

upon HRQL– Most instruments can’t cover all important content

• Disease trajectory includes– Diagnosis (acute anxiety)– Active treatment (various and chronic symptoms)– Disease-free survivorship (emerging social issues and

stress responses, negative and positive)– End of life (emerging physical, social and existential

issues)

• Most instruments have floor and/or ceiling effects

•Item Banking

•Computerized Adaptive Testing (CAT)

Looking ahead 5-10 years:Standardizing Metrics and Improving

Precision

National Item Banks Are Coming

NIH Roadmap Cooperative Group:

Patient Reported Outcome Measurement Information System

(PROMIS)

A Better Mousetrap?

• PROMIS and the future of (some) outcome measures– Fatigue– Pain– Physical Function– Social Role participation– Emotional Distress– ???

www.NIHPROMIS.org